Protein kinases play a critical role in cellular development, differentiation and transformation. One of the largest gene families of non-receptor serine-threonine protein kinases is protein kinase C (PKC). Since the discovery of PKC more than a decade ago, a multitude of physiological signaling mechanisms have been ascribed to the enzyme.
The PKC gene family consists presently of 11 genes which are divided into four subgroups: 1) classical PKCxcex1, xcex21, xcex22 and xcex3, 2) novel PKCxcex4, xcex5, xcex7, and xcex8, 3) atypical PKCxcex6, xcex, xcex7 and "igr" and 4) PKCxcexc. Because of their unique structural features, diverse PKC isoforms are thought to have highly specialized roles in signal transduction in response to physiological stimuli, as well as in neoplastic transformation and differentiation. The xcex1, xcex21, xcex22 and xcex3 isoforms are Ca2+, phospholipid- and diacylglycerol-dependent and represent the classical isoforms of PKC, whereas the other isoforms are activated by phospholipid and diacylglycerol but are not dependent on Ca2+.
From a pharmacological perspective, the PKC isozymes are an exciting target for cancer therapy, as well as for other diseases such as autoimmune diseases, ischemia, and inflammatory diseases (see D. Leszczynski, The Cancer Journal, The role of protein kinase C in regulation of apoptosis: a brief overview of the controversy, 9, number 6, (November-December 1996); R. H. Strasser, et al., Circulation Research, 1999, 85, 1, 77-87). There is also considerable interest in identifying agents that possess selectivity for one or more isozymes, since selective agents may have fewer side effects than agents that act on multiple PKC isozymes.
U.S. Pat. Nos. 5,510,339 and 5,631,267 disclose the use of topical anesthetics to treat bronchial asthma and other eosinophil associated hypersensitivity diseases. Additionally, U.S. Pat. No. 5,837,713 discloses the use of a synergistic combination of a topical anesthetic and a glucocorticoid to treat eosinophil associated pathologies.
U.S. patent application Ser. No. 08/985,613 discloses the use of a sulfonylurea receptor (SUR) binding agent to treat IL-5 mediated pathologies. The application also discloses a method for inhibiting cytokine-induced eosinophil survival or activation with a sulfonylurea receptor binding agent, optionally in combination with one or more topical anesthetics and/or glucocorticoids. The application also discloses a method for treating a disease mediated by IL-5 with an agent that is able to modify (e.g. block) ATP-dependent potassium channels, or a protein with which an ATP-dependent potassium channel interacts (such as a SUR).
Additionally, M. K. Tomoda et al., Physiol. Chem. Phys. and Med. NMR, 1990, 22, 199-210, disclose data suggesting that lidocaine inhibits calcium-activated, phospholipid-dependent protein kinase (PKC); and L. M. Weisenthal et al., Cancer Treatment Reports, 1987, 71, 1239-1243, disclose data suggesting that lidocaine, in combination with one or more other specific agents described therein, may be useful to circumvent acquired drug resistance in HLN. However, L. M. Weisenthal et al. also disclose that local anesthetic agents by themselves have not been confirmed to have activity in clinical human cancer.
Despite the above disclosures, there is a continuing need for novel compounds which can modulate PKC. In particular, there is a need for compounds that are selective for one or more PKC isotypes (e.g. PKCxcex4). Such compounds may be useful, for example, to treat cancer or autoimmune diseases, as well as other diseases that are effected by the activity of PKCxcex4.
In the course of studying the mechanism by which topical anesthetics inhibit cytokine mediated eosinophil survival, applicant discovered that lidocaine binds to and modulates (e.g. inhibits) the effects of the calcium independent PKC isozyme PKCxcex4. Thus, applicant has discovered that lidocaine and other topical anesthetics are useful agents for treating diseases wherein PKCxcex4 is implicated, and modulation (e.g. inhibition) of its activity is desired.
Accordingly, the invention provides a therapeutic method for treating a disease or condition characterized by the pathological proliferation of mammalian cells, comprising administering to a mammal in need of such therapy, an amount of a topical anesthetic, or a pharmaceutically acceptable salt thereof, effective to treat the disease or condition.
The invention also provides a therapeutic method for treating an autoimmune disease comprising administering to a mammal in need of such therapy, an amount of a topical anesthetic, or a pharmaceutically acceptable salt thereof, effective to treat the autoimmune disease.
The invention also provides a method to inhibit the activity of PKCxcex4 in vitro comprising contacting PKCxcex4 with an effective inhibitory amount of a topical anesthetic; or a salt thereof. Such a method is useful as a pharmacological tool to further investigate the actions of PKCxcex4, or to identify agents possessing selectivity for one or more PKC isozymes.
The invention also provides a therapeutic method for inhibiting the activity of PKCxcex4 in a mammal in need of such therapy comprising administering to the mammal, an effective PKCxcex4 inhibitory amount of a topical anesthetic; or a pharmaceutically acceptable salt thereof.
The invention also provides a method for treating a condition or disease in a mammal wherein the activity of PKCxcex4 is implicated and antagonism of its action is desired comprising administering to the mammal, an amount of a topical anesthetic, or a pharmaceutically acceptable salt thereof, effective to inhibit PKCxcex4 so as to treat the condition or disease.
The invention also provides the use of a therapeutically effective amount of a topical anesthetic; or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease wherein PKCxcex4 is implicated and modulation of its activity is desired (e.g. cancer, an autoimmune disease, ischemia, or an imflammatory disease).
In the therapeutic methods of the invention, a topical anesthetic or a pharmaceutically acceptable salt thereof can be administered in combination with one or more other therapeutically active agents (e.g. chemotherapeutic agents), or can be administered alone (as the sole therapeutically active agent for treating a given disease).